Oxazinoindole-and thiazinoindole derivatives

ABSTRACT

OXAZINOINDOLE DERIVATIVES CHARACTERIZED BY HAVING AN AMINO(LOWER)ALKYL RADICAL ATTACHED TO THE 1 POSITION OF A 1H-1,4-OXAZINO(4,3-A)INDOLE NUCLEUS ARE DISCLOSED. THE AMINO PORTION OF THE AMINO(LOWER)ALKYL RADICAL MAY BE FURTHER SUBSTITUTED WITH ONE OR TWO LOWER ALKYL GROUPS OR INCORPORATED IN A HETEROCYCLIC AMINE RADICAL. THE DERIVATIVES ARE SUBSTITUTED FURTHER AT POSITIONS 1 AND 10 AND MAY BE OPTIONALLY SUBSTITUTED AT POSITIONS 3. 4, 6, 7, 8 AND 9. THE OXAZINOINDOLE DERIVATIVES OF THIS INVENTION ARE USEFUL ANTIDEPRESSANT AND ANTIULCER AGENTS. METHODS FOR THE PREPARATION AND USE OF THESE DEIVATIVES ARE ALSO DISCLOSED.

United States Patent 3,833,575 OXAZINOINDOLE- AND THIAZINOINDOLEDERIVATIVES Christopher A. Demerson, Leslie G. Humber, George Santroch,Thomas A. Dobson, and Ivo JlIkOVSkY, Montreal, Quebec, Canada, assignorsto Ayerst, Mc- Kenna and Harrison Limited, Montreal, Quebec, Cauada NoDrawing. Filed Feb. 14, 1972, Ser. No. 226,287

Int. Cl. C07d 87/38 US. Cl. 260-243 R 1 Claim Oxazinoindole derivativescharacterized by having an amino(lower)alkyl radical attached to the 1position of a 1H-1,4-oxazino[4,3-a]indole nucleus are disclosed. Theamino portion of the amino(lower)alkyl radical may be furthersubstituted with one or two lower alkyl groups or incorporated in aheterocyclic amine radical. The derivatives are substituted further atpositions 1 and and may be optionally substituted at positions 3 4, 6,7, 8 and 9. The oxazinoindole derivatives of this invention are usefulantidepressant and antiulcer agents. Methods for the preparation and useof these derivatives are also disclosed.

BACKGROUND OF THE INVENTION 1. Field of Invention This invention relatesto novel oxazinoindole and thiazinoindole derivatives, to processes fortheir preparation and to intermediates used in these processes. Forconvenience, further reference in this specification will be made tothese compounds as oxazinoindole derivatives.

More specifically, the present invention relates to oxazinoindolederivatives possessing valuable pharmacologic properties. For example,these derivatives exhibit useful antidepressant properties at dosageswhich do not elicit undesirable side effects. Furthermore the presentderivatives exhibit properties useful for the treatment and preventionof ulcers. The combination of these pharmacologic properties togetherwith a low order of toxicity render the oxazinoindoles of the inventiontherapeutically useful.

2. Description of the Prior Art Very little attention has been given to1,4-oxazino- [4,3-a]indole derivatives prior to this disclosure. In thefew reports that do exist, such as the reports by J. A. Elvridge and F.S. Spring, J. Chem. Soc., 2935 (1949) and W. R. "Smith and R. Y. Moir,Can. J. Chem., 30, 411 (1952), the oxazinoindole derivatives are treatedmore in the manner of chemical curiosities In these instances, theoxazinoindoles are distinguished readily from the compounds of thisinvention by having the pyran portion of their ring system at a higheroxidation state.

SUMMARY OF THE INVENTION The oxazinoindole derivatives of this inventionare characterized by having an amino(lower)alkyl radical attached to a1H-1,4-oxazino[4,3-a1indole nucleus. The preferred derivatives of thisinvention are represented by formula I,

Ice

in which R is lower alkyl or lower cycloalkyl; R R R and R are the sameor different selected from the group consisting of hydrogen or loweralkyl; R is hydrogen, lower alkyl, hydroxy, lower alkoxy, loweralkanoyloxy, nitro or halo; R is lower alkyl; X is oxy or thio; and AllNRR is an amino(lower)alkyl radical in which Alk is an alkylene selectedfrom the group consisting of CR R CR R CR R c m uc iz isc m is and CR RCR R CR R CR R in which R R R R R R R and R are hydrogen or lower alkyl,and R and R are either the same or different selected from the groupconsisting of hydrogen and lower alkyl, or R and R together with thenitrogen atom to which they are joined form a heterocyclic amine radicalselected from the group consisting of l-pyrrolidinyl, piperidino,morpholino, piperazino. 4-(lower alkyD-lpiperazinyl and4-[hydroxy(lower)alkylJ-l-piperazinyl.

DETAILED DESCRIPTION OF THE INVENTION The term lower alkyl as usedherein contemplates straight chain alkyl radicals containing from one tosix carbon atoms and branched chain alkyl radical containing up to fourcarbon atoms and includes methyl, ethyl, propyl, isopropyl, butyl,isobutyl, Z-methylpentyl and the ike.

The term lower cycloalkyl as used herein contemplates saturated cyclichydrocarbon radicals containing from three to six carbon atoms andincludes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term lower alkoxy as used herein contemplates both straight andbranched chain alkoxy radicals containing from one to four carbon atomsand includes methoxy, ethoxy, isopropoxy, t-butoxy and the like.

The term lower alkanoyloxy as used herein contemplates both straight andbranched chain alkanoyloxy radicals containing from two to six carbonatoms and includes acetoxy, propionyloxy, piyaloyloxy, hexanoyloxy andthe like.

The term halo as used herein contemplates halogens and includesfluorine, chlorine, bromine and iodine.

The compounds of formula :I are capable of forming acid addition saltswith pharmaceutically acceptable acids. Such acid addition salts areincluded within the scope of this invention.

The acid addition salts are prepared by reacting the base form of theappropriate compound of formula I with either one or two equivalents,depending on the number of basic nitrogens in the compound, orpreferably with an excess of the appropriate acid in an organic solvent,for example, ether or an ethanol-ether mixture. These salts, whenadministered to mammals, possess the same pharmacologic activities asthe corresponding bases. For many purposes it is preferable toadminister the salts rather than the base compounds. Among the acidaddition salts suitable for this purpose are salts such as the sulfate,phosphate, lactate, tartrate, maleate, citrate, hydrobromide andhydrochloride. Both the base compoounds and the salts have the distinctadvantage of possessing a relatively low order of toxicity.

Also included in this invention are the stereochemical isomers of thecompounds of formula I which result from asymmetric centers, containedtherein. These isometric forms may be prepared by different methods andare purified readily by crystallization or chromatography.

Individual optical isomers, which might be separated by fractionalcrystallization of the diastereoisomeric salts formed thereof, forinstance, with dor 1- tartaric acid or D-(+)-a-bromocamphor sulfonicacid, are also included.

3 Antidepressant Activity The useful antidepressant activity of thecompounds of formula I and their acid addition salts withpharmaceutically acceptable acids may be demonstrated in standardpharmacologic tests, such as, for example, the tests described by F.Hafliger and V. Burckhart in Psychopharmacol'ogical Agents, M. GordonEd., Academic Press, New York and London, 1964, pp. 75-83.

More specifically, as noted in the latter reference the antidepressantproperties of a compound may be demonstrated by its capacity toantagonize the depressant effects of reserpine. Furthermore, it is welldocumented that reserpine in animals produces a model depression whichcan be used for detecting antidepressant properties. Accordingly, thecompounds of the present invention antagonize reserpine effects in miceat doses ranging from about 1 to 100 mg./kg. Several of the preferredcompounds, for instance:

1,10-dimethyl- 1-[2-(ethylamino) ethyl]-3,4-dihydro- 1H-l,4oxazin=o-[4,3-a]indole hydrobromide (Example 284) 1, IO-dimethyll-(Z-dimethylamino) ethyl] -3 ,4-dihydro- I 1H-1,4-oxazino[4,3-a]indolehydrochloride (Example 284)1-(3-aminopropyl)-1,10-dimethyl-3,4dihydro-1H-1,4-

oxazino- [4,3-a] indole hydrochloride (Example 2861,lO-dimethyl-1-[3-(methylamino)propyl]-3,4-dihydrol-H-1,4-oxazino[4,3-a]indolehydrochloride (Example 285) and 1,10-dimethyl-l-[3-(dimethylamino)propyl] -3,4-dihydrolH-.l,4-oxazino[4,3-a]indolehydrochloride (Example 287),

antagonize the effects of reserpine in mice at dose ranges from about 1to mg./ kg.

When the compounds of this invention are used as antidepressants inwarm-blooded mammals, e.g. rats and mice, they may be used alone or incombination with pharmacologically acceptable carriers, the proportionof which is determined by the solubility and chemical nature of thecompound, chosen route of administration and standard biologicalpractice. For example, they may be administered orally in solid formcontaining such excipients as strach, milk sugar, certain types of clayand so forth. They may also be administered orally in the form ofsolutions or they may be injected parenterally. For parenteraladministration they may be used in the form of a sterile solutioncontaining other solutes, for example, enough saline or glucose to makethe solution isotonic.

The dosage of the present therapeutic agents will vary with the form ofadministration and the particular compound chosen. Furthermore, it willvary with the particular host under treatment. Generally, treatment isinitited with small dosages substantially less than the optimum dose ofthe compound. Thereafter, the dosage is increased by small incrementsuntil the optimum effect under the circumstances is reached. In general,the compounds of this invention are most desirably administered at aconcentration level that will .generally afford effective resultswithout causing any harmful or deleterious side effects and preferablyat a level that is in a range of from about 0.1 mg to about 50 mg perkilo per day, although as aforementioned variations will occur. However,a dosage level that is in the range of from about 0.5 mg to about 25 mgper kilo per day is most desirably employed in order to achieveeffective results.

Antiulcer activity The compounds of formula I of this invention possessanother useful pharmacologic property; that is, they are usefulantiulcer agents. More particularly, the said compounds of thisinvention exhibit antiulcer activity in stand ard pharmacologic tests,for example, the test described by D. A. Brodie and L. S. Valitski,Proc. Soc. Exptl. Biol.

Med., 113, 998 (1963), based on the prevention of stressinduced ulcers.

When the compounds of formula I are employed as antiulcer agents, theymay be formulated and administered in the same manner as described abovefor their use as antidepressant agents.

Processes For the preparation of the oxazinoindoles of this invention weprefer to use as starting materials the compounds of formula II,

l H II in which R and R are as defined in the first instance.

The starting materials of formula II are either well known, for example,skatole and B-ethylindole, or they may be prepared from indole or knownindole derivatives, for example, see P. L. Julian, er al., HeterocyclicCompounds, R. C. Elderfield, Ed., Vol. '3, John Wiley and Sons, Inc.,New York, 1952, p. 1, according to the method of R. Robinson, et al.,described in US. Patent No. 2,407,452, issued September 10, 1946.

The starting material of formula II is then converted to the keyintermediate of formula III,

in which R R R R R and R are as defined in the first instance and X ishydroxy or mecapto.

This conversion may be effected by several methods. One general methodinvolves reacting the appropriate lithium derivative of the startingmaterial of formula II with ethylene oxide or an appropriate lower alkylsubstituted ethylene oxide to afford the desired intermediate of formulaIII in which X is hydroxy. The desired intermediates may also beobtained by treating the appropriate starting material of formula IIwith the appropriate ethylene oxide derivative according to theprocedure of M. Julia, et al., Bull, Soc. Chim. Fr., 2291 (1966).

The lower alkyl substituted ethylene oxides are prepared by knownmethods; for example, see V. Franzen and H. E. Driesen, Chem. Ber. 96,1881 (1936).

An alternative method for the prepartion of intermediates of formula IIIin which R and R are hydrogen involves treating the starting material offormula II with an whaloacetic acid lower alkyl ester of formula LCR ROOO-(lower alkyl) in which L is halo and R and R are as defined in thefirst instance, in the presence of a suitable proton acceptor and usingpreferably an inert solvent for the reaction. Tlhe u-haloacetic acidlower alkyl esters are well known, for example see Rodds Chemistry ofthe Carbon Compounds, S. Coffey, Ed., Vol. Ic, 2nd ed, ElsevierPublishing (30., Amsterdam, 1965, pp. 201-205. Suitable proton acceptorsinclude sodium hydride, alkali metal carbonates and triethylamine.Suitable inert solvents include tetrahydrofuran, benzene, toluene anddimethylformamide. Preferred conditions for the N-alkylation include theuse of sodium hydride as a proton acceptor and tetrahydrofuran as aninert solvent. Although the optimum temperature and reaction time willvary depending on the reactants employed, the reaction is generallyperformed at the boiling point of the reaction mixture for a period of30 minutes to 48 hours.

The indole-1-acetic acid lower alkyl ester derivative obtained by theabove N-alkylation reaction is thereafter hydrolyzed, preferably with asolution of potassium hydroxide in methanol water, to give thecorresponding indole-1-acetic acid derivatives which on reduction withlithium aluminum hydride affords the desired intermediate of formula IIIin which R and R are hydrogen and X is hydroxy.

Again alternatively, the latter indole-1-acetic acid derivative may alsobe reacted with two equivalents of a lower alkyl Grignard reagent, forexample, methyl magnesium bromide, to give, after hydrolysis of themagnesium-halogen derivative, the desired intermediates of formula III(R =R =lower alkyl and X =hydroxy), see L. F. Fieser and M. Fieser,Advanced Organic Chemistry, Reinhold Publishing Corp., New York, 1961,p. 272.

When the corresponding intermediates of formula III in which X ismercapto are desired, a procedure similar to that described by N. N.Suvorov and V. N. Buyanov, Khim.-Farm. ZH., 1 (1967), [Chem. Abstr. 67,7347431 (1967)], for converting 3-(2-bromoethyl)-indole toindole-3-ethanethiol, may be employed. More particularly, the aboveintermediate of formula III in which X is hydroxy is treated withphosphorus tribromide in an inert solvent, for example, ether or carbontetrachloride, followed by treatment of the product with sodium orpotassium thiosulfate to afford the Corresponding sodium or potassium,B-(l-indolyD-ethyl thiosulfate derivative, respectively. Treatment ofthe latter product with strong alkali, for example, sodium or potassiumhydroxide, yields the corresponding bis-[w-(indolyl)ethylldisulfidederivative. Finally reduction of the latter compound with lithiumaluminum hydride gives the desired intermediate of formula III in whichX is mercapto.

Alternatively, the starting materials of formula III in which R and Rare hydrogen and X is mercapto may be prepared by oxiding thecorresponding intermediates of formula III in which X is hydroxy,described above, with N,N-dicyclohexylcarbodiimide and dimethylsulfoxide in the presence of a suitable acid, for example,trifiuoroacetic acid, see K. E. Pfitzner and J. G. Mofiat, J. Amer.Chem. Soc., 87, 5670 (1965), to give the corresponding aldehydederivative. The same aldehyde derivative may also be obtained byN-alkylation of the appropriate starting material of formula II with anappropriate u-halo-acetaldehyde derivative (see Rodds Chemistry of theCarbon Compounds, cited above, Vol. 1c, pp. 2426) according to theconditions described above for N-alkylation with ahaloacetic acid loweralkyl esters.

The latter aldehyde derivative is converted to its correspondinggem-dithiol derivative with hydrogen sulfide, which is reduced withlithium aluminum hydride, according to the method of T. L. Cairns, eral., J. Amer. Chem. Soc., 74, 3982 (1952), to yield the desired startingmaterial of formula III.

It should be noted that the preceding processes may not be entirelypractical for the preparation of the compounds of formula III in which Xis hydroxy or mercapto and R is hydroxy or lower alkanoyloxy. For thisreason, the preferred starting materials of formula II for the ultimatepreparation of the compounds of formula I in which R is hydroxy or loweralkanoyloxy are the corresponding compounds of formula II in which R isbenzyloxy, i.e. a hydroxyl with a protecting benzyl group or othersuitable protecting group (see I. F. W. McOmie, Advances in OrganicChemistry, Vol. 3, R. A. Raphael, et 111., Ed., Interscience Publishers,New York, 1963, pp. 191-294). After the appropriate transformationsdescribed below, the benzyloxy group is romoved by hydrogenation, in thepresence of a catalyst, for example, palladium on carbon, just prior toaffording the desired corresponding compound of formula I in which R ishydroxy. The latter may be converted if desired to the correspondingcompound of formula I in which R is lower alkanoyloxy by conventionalmeans, for example, by treatment with the appropriate lower alkanoicanhydride preferably in the presence of pyridine.

The above described intermediate of formula III in which R R R R R R andX are as defined in the 6 first instance are now subjected to a keyreaction comprising the treatment of said starting materials with acompound of formula in which R is as defined in the first instance and Zis selected from the group consisting of:

(a) COOR and Alk COOR in which R is hydrogen or lower alkyl and Alk isan alkylene selected from the group consisting of CR R CR R CR R andCR10R11CR12R13CR14R15 wherein 10 11 12 13 14 and R are hydrogen or loweralkyl, (b) CONR R and Alk CONR R in which Alk R and R are as definedabove, (c) CH OCOR and Alk --CH OCOR in which R is hydrogen or loweralkyl and Alk is as defined above, (d) Alk L in 'which Alk is analkylene selected from the group consisting of CR R CHRCRIORIICRIZRBCHRM and CR "R CR R CR R CHR wherein and R are as definedabove and L is halo,

(c) Alk NR COR in which Alk and R are as defined in the first instanceand R is hydrogen or lower alkyl containing from one to five carbonatoms, and

(f)) Alk-NO in which Alk is as defined in the first instance, in thepresence of an acid catalyst to yield the compounds of formula V inwhich R R R R R R, R", X and Z are as defined above.

Thereafter the appropriate compound of formula V is converted to thedesired oxazinoindole of formula I according to the processes describedhereinafter.

In practising the condensation (III+VI V) we have found it preferable touse a solvent as a reaction medium.

- Any solvent inert to the reaction conditions may be used.

Suitable solvents include aromatic hydrocarbons, for ex-.

ample, benzene or toluene, ethers and cyclic ethers, for example,diethyl ether, dioxan or tetrahydrofuran, halogenated hydrocarbons, forexample methylene dichloride or carbon tetrachloride and the like.Benzene and toluene are especially convenient and practical for thisuse. A variety of suitable acid catalysts may be used for thiscondensation, for example, the type of catalyst used in a Friedel-CraftsReaction, i.e. p-toluenesulfonic acid, aluminum chloride, phosphoruspentoxide, boron trifluoride, zinc chloride, hydrochloric acid,perchloric acid, trifluoroacetic acid, sulfuric acid and the like.p-Toluenesulfonic acid, aluminum chloride, boron trifluoride andphosphorus pentoxide are included among the preferred acid catalysts.The amount of acid catalyst used is not especially critical and mayrange from 0.01 molar equivalents to molar equivalents; however, a rangeof from 0.1 to 10 molar equivalents is generally preferred. The time ofthe reaction may range from 10 minutes to 60 hours, with the preferredrange being from one-half to 24 hours. The temperature of the reactionmay range from 20 C.

to the boiling point of the reaction mixture. Preferred temperatureranges include 20 to 120 C.

A more detailed description of the preparation of the above intermediatecompounds of formula V and a description of their subsequent conversionto the oxazinoindole derivatives of formula I are disclosed below. Forconvenience these descriptions are catagorized into sections accordingto the group selected for Z for the intermediate.

(a) Preparation and Conversion of Intermediates of Formula V -(Z=COO:Rand Alk COOR Intermediates of formula V (Z=COOR and Alk COOR in which Ris hydrogen or lower alkyl and Alk is as defined in the first instanceand R R R R R R, R and X are as defined in the first instance) arereadily obtained by the condensation (III-i-IV V) by using ketoacid orketoesters of formula II n -o-z in which R is as defined in the firstinstance and Z is COOR or AlkCOOR as defined above together with theintermediate of formula III.

Generally comparable yields of product are obtained in this process wheneither the ketoacid or the corresponding ketoester is used. However, inthe case where it is desired to prepare an acid compound of formula V inwhich Z is Alk COOR wherein Alk is CR R and R is hydrogen (i.e., an acidintermediate of formula V), it is preferable to first condense theappropriate ii-ketoester of formula IV rather than the corresponding,B-ketoacid and then hydrolyze the resulting ester product to give thedesired acid compound.

Moreover, in the general practice of this invention it is often moreconvenient to prepare the acid compounds of formula V by using theketoester instead of the ketoacid in this process and then hydrolyze theresulting ester product to the desired acid, the reason being simplythat the ketoesters are generally more readily available eithercommercially or by synthesis.

Compounds of formula V in which Z COOR or AIk COOR wherein Alk is asdefined in the first instance and R is lower alkyl, i.e. esterintermediates of formula V, are hydrolyzed readily to theircorresponding acids of formula V by treatment with a suitable alkali,for ex ample, potassium hydroxide or sodium carbonate, in aqueousmethanol or aqueous ethanol or by treatment with lithium iodide in asuitable organic solvent, for example,

collidine, see L. F. 'Fieser and M. Fieser, Reagents for OrganicSynthesis, John Wiley and Sons, Inc., New York, 1957, pp. 615-617.

The 11-, 5-, 'yand fi-ketoacids and -ketoesters of formula III areeither known, for example, ethyl pyruvate, levulinic acid, ethyla,a-dimethylacetoacetate and {QB-dimethyl-levulic acid or they may beprepared by known methods described in general organic chemistrytextbooks. For example, a comprehensive review on the properties andpreparation of such oc-, 5-, 'yand B-ketoacids and -ketoesters may befound in Rodds Chemistry of the Carbon Compounds, cited above, Vol. Id,pp. 226-274.

Thereafter these intermediate acids and esters of formula V areconverted to compounds of formula I in which R R R R R R", R" and X areas defined in the first instance and AlkNR R is an amino(lower)alkyl inwhich Alk is CH or Alk CH wherein Alk is as defined in the firstinstance and R and R are as defined in the first instance.

In the case where the acid intermediate of formula V 8 by treatment withthe appropriate amine of formula HNRR in which R and R are as defined inthe'first instance, for example, ammonia, methylamine or dimethylamine,to yield the corresponding amide of formula V in which Z is CONR R orAlk CONR R wherein Alk R and R are as described in the first instance.

Alternatively, the latter amides are also obtained by treating the esterintermediates of formula V, described above, with the appropriate amineaccording to known amidation methods, for example, see A. L. F. Beckwithin The Chemistry of Amides, J. Zalicky, Ed., Interscience Publishers,New York, 1970, pp. 96-105.

Thereafter, the amides so obtained are reduced with a suitable complexmetal hydride to yield the desired oxazinoindoles. Examples of suitablecomplex metal hydrides are lithium aluminum hydride, lithium aluminumhydride-aluminum chloride, aluminum hydride-aluminum chloride, diboraneand sodium borohydride-aluminum chloride. Lithium aluminum-hydride ispreferred.

Two aspects of this latter reduction of the amides are worth noting. Thefirst aspect relates to the reduction of the above amides of formula Vin which Z is CONR R or Alk CONR R wherein Alk is as defined in thefirst instance, R is hydrogen and R is lower alkyl, i.e. secondaryamides, to their corresponding oxazinoindoles of formula I, i.e.secondary amines. In this case a modification of the above process inthe following manner is among the preferred procedures. Theaforementioned acid or ester intermediate of formula V is reacted withan amine of formula HNR R in which R is benzyl and R is lower alkylcorresponding to the R of the desired amine. This step is performedaccording to the amidation step described above. The resulting amide isthen reduced with a complex metal hydride according to the aboveprocedures. Thereafter the benzyl group is removed by hydrogenolysis inthe presence of a catalyst, preferably 10% palladium on carbon, toafford the desired secondary amine compound of formula I.

The second aspect relates to a more general modification for thereduction of the above amides of formula V in which Z is CONR R or AlkCONRR wherein All-: R and R is as defined in the first instance.

This modification is applicable to the reduction of the tertiary,secondary and primary amides and is a preferred modification for thereduction of the latter two. In practising this modification, theaforementioned amide of formula V is treated with triethyloxoniumfiuoroborate, see R. F. Borch, Tetrahedron Letters, No. l, 61 (1968), ordimethyl sulfate, see H. Bredereck, et al., Chem. Ber., 98, 2.754(1965), in an inert solvent, for example, methylene dichloride, wherebythe corresponding iminoether fiuoroborate or methyl sulfate salt isobtained, respectively. Subsequent reduction of the salt thus obtainedwith a complex metal hydride according to the procedure described abovefor reducing amides yields the desired oxazinoindole of formula I.Alternatively, the above fluoroborate or methyl sulfate salt derivedfrom a secondary or primary amide may be decomposed by base treatment,for example, with 10% sodium hydroxide solution or triethylamine, togive the corresponding iminoether derivative which is then reduced in alike manner to the desired oxazinoindole.

When applying the aforementioned steps in the preparation of compoundsof formula I in which R is hydroxy or lower alkanoyloxy, it ispreferable to use corresponding intermediates in which R is benzyloxyfollowed by the appropriate transformations as noted previously to yieldthe desired compounds of formula I.

(b) Preparation and Conversion of Intermediates of Formula V (Z=CONR Rand Al'k CONR R The intermediates of formula V in which Z is CONR R andAlk CONR R wherein R R and Alk are as defined in the first instance,described in the previous section, are also obtained directly byutilizing the appropriate starting materials of formula III and 01-, 6-,'y-, or a-ketoamides of formula in which R is as defined above and Z isCONR R or Alk CONR R in which Al'k R and R are as defined above. Theketoarnides required for this condensation are either known, forexample, pyruvamide or mot-dimethylacetoacetainide, or they may beprepared by known methods, for instance, see Rodds Chemistry of theCarbon Compounds, cited above, Vol. ld, pp. 226 274.

Thereafter these amides of formula V are converted by the reductionprocess, described above, to the compounds of formula I in which R R R RR R, R and X are as defined in the first instance and Alk-NR R isamino(lower)alkyl in which Alk is CH or Alk -CH wherein Alk is asdefined in' the first instance and R and R are as defined in the firstinstance.

(c) Preparation and Conversion of Intermediates of Formula V (Z CI-IOCOR and Alk CH OCOR Intermediates of formula V in which Z is CH OCORand Alk CH OCOR in which Alk and R are as defined in the first instance,are obtained when a starting material of formula III is condensed with aketo alcohol lower alkanoic acid ester of formula R COCH OCOR or R COAlkCH OCOR in which R Alk and R are as defined in the first instance in thepresence of a suitable acid catalyst according to the conditionsdescribed above for the condensation (III-t-IV+V). The ketoalcohol loweralkyl esters are either known, for example, acetonyl acetate orS-acetoxy-pentan-Z-one, or may be prepared by known methods, forinstance, see Rodds Chemistry of the Carbon Compounds, cited above, Vol.1d, pp. 49-54.

These intermediates of formula V may then be utilized for thepreparation of compounds of formula I of this invention in the followingmanner. The intermediate is hydrolyzed with an aqueous alcoholicsolution of a suitable alkali, for example, sodium hydroxide in aqueousmethanol to afford the corresponding primary alcohol. It should be notedthat the latter primary alcohols may also be obtained by the directreduction of the intermediate acids and esters of formula V, describedherein in section (a), using a suitable complex metal hydride asdescribed therein. The primary alcohol is then oxidized to thecorresponding aldehyde. Although a variety of methods are known for theoxidation of a primary alcohol to its corresponding aldehyde, see forexample, Rodds Chemistry of the Carbon Compounds, cited above, Vol; 10,pp. 4-10, we have found that the method of K. E. Pfitzner and J. G.Moffat, J. Am. Chem. Soc., 87, 5670 (1965), usingN,N-dicyclohexylcarbodiimide and dimethyl sulfoxide in the presence of asuitable acid, for example, trifiuoroacetic acid, is both efficaciousand convenient. Thereafter the aldehyde is reacted with an amine offormula I-INR R in which R and R are as defined in the first instanceaccording to the method of K. N. Campbell, et al., J. Amer. Chem. Soc.,70, 3868 (1948) in the case when the amine used is ammonia or a primaryamine, or according to the method of N. J. Leonard and J. V. Paukstelis,J. Org. Chem., 28, 1397 (1963) when the amine is a secondary amine, togive the corresponding Schiff base or immonium salt, respectively. Theproduct so obtained is reduced with sodium borohydride, see E'.Schenker, Angew. Chem., 73, 81 (1961), to yield compounds of formula Iin which R R R R R R R and X are as defined in the first instance Alk-NRR is an amino(lower)alkyl in which Alk is CH or Alk1CH wherein Alk is asdefined in the first instance and R and R are as defined in the firstinstance.

Alternatively, the latter compounds of formula I may be obtained byconverting the above corresponding alcohol to a reactive intermediatesuch as the corresponding halide, mesylate or tosylate, which may thenbe reacted with two or more molar equivalents of an amine of formula HNRR in which R and R are as defined in the first instance. Preferably thisreaction is performed in a suitable inert solvent, for example,tetrahydrofuran, at 40 to 100 C. or at the boiling point of the reactionmixture for a period of eight to 24 hours. In connection withalkylations of amines of formula HNR R in which R is hydrogen and R islower alkyl as disclosed herein, it is generally more advantageous withrespect to yields to perform the alkylation with the corresponding N-benzyl derivative of said amine, i.e., an amine of formula HNR R inwhich R is benzyl and R is lower alkyl. Thereafter, when all appropriatetransformation have been performed, the N-benzyl group may be removed byhydrogenolysis with a catalyst, preferably 10% pal-. ladium on carbon,to give the desired compounds of formula I.

Alternatively, the above aldehyde is oxidized with a suitable oxidizingagent to yield the corresponding acid intermediates of formula Vdescribed in section (21). Although a variety of suitable oxidizingagents may be used for this purpose, for example, silver oxide, alkalinepermanganate, hydrogen peroxide, the use of silver oxide according tothe method of M. Delpine and P. Bonnet, Compt. rend., 149, 39 (1909) ispreferred.

Again alternatively, the above aldehyde is converted to its oxime whichon reduction with a complex metal hydride yields the correspondingprimary amine of formula I in which R R R R R R R and X are as definedin the first instance and AlkNR R is an amino(lower)alkyl in which Alkis CH or Alk CH wherein Alk is as defined in the first instance and Rand R are hydrogen.

In turn these latter compounds of formula I may be further N-alkylatedon the nitrogen of the primary amine with the appropriate lower alkylhalide to the corresponding compounds of formula I in which Y is AlkNR Rwherein Alk is CH or Alk CH wherein Alk is as defined in the firstinstance and R is hydrogen or lower alkyl and R is lower alkyl (i.e.secondary or tertiary compounds in which R or R are either or bothmethvl,

an alternative alkylation method comprises reacting the appropriatecorresponding primary or secondary amine with an aqueous mixture of asubstantial excess of formaldehyde and formic acid according to theconditions of the 'Eschweiler-Clarke reaction, see M. L. Moore, OrganicReactions, 5, 301 (1949), whereby N-methylation is effected.

Another N-alkylation method which may be applied to the above primaryand secondary amines involves acylation with a lower alkanoic anhydrideor acid halide and subsequent reduction of the resulting amide.

Furthermore, the above primary amines may be used to preparecorresponding compounds of formula I in which R and R together with thenitrogen atom to which they are joined form a heterocyclic amine radicalas defined in the first instance. When used in this manner the'uri-maryamines are subjected to known. N-alkylation methods, for example, seeMethod I described by R. B. Moffet, J. Org. Chem., 14, 862 (1949, withthe appropriate a,w-dibromides, for example, tetramethylene dibromide,pentamethylene dibromide, bis(2-chloroethyl)ether, bis- 1 l(2-chloroethyl)benzylamine followed by hydrogenation in the presence of10% palladium on carbon to remove the protecting benzyl group, abis(2-chloroethyl) lower alkylamine or abis(2-chloroethyl)-N-[hydroxy(lower) alkyl]amine, to give thecorresponding desired compound of formula I in which R and R togetherwith the nitrogen atom to which they are joined form a heterocyclicamine radical, i.e., a pyrrolidino, piperidino, morpholirzo, piperazino,4-(lower)alkyl-l-piperazinyl or 4- [hydroxy (lower) a1lyl]-1-piperazinyl, respectively.

((1) Preparation and Conversion of Intermediates of Formula V (Z=Alk -L)Intermediates of formula V in which Z is Alk -L wherein Alk and L are asdefined in the first instance, are obtained when a starting material offormula III is condensed with a ,6, 'y or E-haloketone of formula inwhich R Alk and L are as defined in the first instance in the presenceof a suitable acid catalyst according to the conditions described abovefor the condensation (III-|-IV+V). The haloketones are either known, forexample, 4-chlorobutan-2-one, or they may be prepared by known methods,for instance, .see Rodds Chemistry of Carbon Compounds, cited above,Vol. 1c, pp. 70-71 and Methoden der Organischen Chemie, Houben-Weyl, E.Muller, -Ed., Vol. V/3, Georg Thieme Verlag, Stuttgart, 1962, pp.511-1076.

Thereafter these intermediates of formula V are treated with a two molarexcess of an amine of formula in which R and R are as defined in thefirst instance to yield the compounds of formula I in which R R R R R RR and X are as described in the first instance, and -AlkNR R is anamino(lower)-alkyl in which Alk is Alk as defined in the first instanceand R and R are as defined above. Preferably this reaction is performedin a suitable inert solvent, for example, tetrahydrofuran at the boilingpoint of the reaction mixture for a period of 8 to 24 hours.

(e) Preparation and Conversion of Intermediates of Formula V (Z=AlkNRCOR Intermediates of formula V in which Z is AlkNR COR wherein Alk, Rand R are as defined in the first instance are readily obtained by thecondensation (I1I+IV- V) by using ketoamides of formula in which R Alk,R and R are as defined in the first instance together with theappropriate starting material of formula MI.

The ketoamides used herein are either known, for example,formamidoacetone [A. T reibs and W. Sutter, Chem. Ber., 84, 96 (1951)],see also R. H. Wiley and O. H. Borum, J. Amer. Chem. Soc., 70, 2005(1948), or may be prepared by known procedures, for example, seeMethoden der Organischen Chemie, cited above, Vol. XI/l, 1957,especially pp. 58-62, 285-289 and 508-509, and F. F. Blicke, OrganicReactions, 1, 303 (1942).

Thereafter, reduction with a complex metal hydride converts the instantintermediates of formula V to oxazinoindoles of formula I in which R R RR R R R", and X are as described in the first instance, and -Alk-NR R isan amino(lower)alkyl in which Alk and R are as defined in the firstinstance and R is lower alkyl.

(f) Preparation and Conversion of Intermediates of Formula V (Z=Alk-NOIntermediates of formula V in which Z is Alk-N0 wherein Alk is asdefined in the first instance, are obtained 1.2 by the condensation(I1I+IV- V) when the starting materials of formula III and appropriateo-, 13-, 'y-, and 5- nitroketones of formula in which R and Alk are asdefined in the first instance are employed therein in the presence of asuitable acid catalyst. In this case trifluoroacetic acid is thepreferred acid catalyst.

The nitroketones used herein are either known, for example,1-nitro-2-propanone, N. Levy and C. W. Scaife, J. Chem. Soc., 1100(1946) and 5-nitro-2-hexanone, H, Shechter, et al., J. Amer. Chem. Soc.74, 3664 (1952) or they may be prepared by known methods, for example,see Levy and Scaife, cited above, Shechter, et al. cited above, RoddsChemistry of Carbon Compounds, cited above, Vol. 10, pp. 71-72 andMethoden der Organischen Chemie, cited above, Vol. X/l, 1971, p. 203.

Thereafter, these intermediates of formula V are reduced with a complexmetal hydride, preferably lithium aluminum hydride, to afford theoxazinoindoles of formula I in which R R R R R R R and X are as definedin the first instance, and AlkNR R is an amino(lower)alkyl in which Alkis defined in the first instance and R and R are hydrogen.

If desired the latter compounds may be N-alkylated according to themethods described in section (c) to give the compounds of formula I inwhich R R R R R R R and X are as defined in the first instance and Alk-NR R is an amino(lower)alkyl in which Alk, R and R are as defined in thefirst instance.

The following examples illustrate further this invention.

EXAMPLE 1 3-Methylindole-1-ethanol(III: R R R R and R =H, R =CH and X:OH)

Procedure A:

Commercial n-butyl lithium in hexane (3.05 mole) is diluted with 1000ml. of dry tetrahydrofuran (THF). To this cooled (-10 to 0 C.) solutionthe starting material of formula II, skatole (393 g., 3.0 mole) in 1000ml. of dry THF, is added dropwise. The reaction is stirred at the samelow temperature for 1 hour and then 300 ml. of ethylene oxide in 300 ml.of dry THF is added to the mixture. The temperature of the reaction isallowed to rise to room temperature and at this temperature the reactionis stirred overnight.

TH'F is evaporated and the residue is dissolved in methylene chlorideand washed with concentrated H Cl. The methylene chloride solution isthen washed with 10% sodium bicarbonate, water and dried (MgSO Thesolvent is evaporated and the product distilled at reduced pressure togive the title compound, b.p. 124 C./ 0.25 mm.

Procedure B:

The starting material of formula II, skatole (35 g., 0.276 mole) in 300ml. of dimethylformamide (DMF) is added dropwise to stirred mixture ofsodium hydride (14.0 g., 55% oil dispension) in 325 ml. of DMF. Themixture is heated at 40 C. for two hours. After cooling in an ice-waterbath ethyl bromoacetate (116.5 g., 0.7 mole) is added dropwise keepingthe temperature below 20 C. After the addition, stirring is continuedfor five minutes, and then water added cautiously to destroy any excesshydride. The reaction mixture is partitioned between water and ether.The ether layer washed with water, dried (MgSO and evaporated underreduced pressure.

The residue, 3-methyl-indole-l-acetic acid ethyl ester, is dissolved in900 ml. of methanol, potassium hydroxide g.) in 400 ml. of 1:1methanol-H O is 13 then added. The mixture is stirred at roomtemperature for 1 /2 hours. The methanol is evaporated under reducedpressure. The residue is diluted with water (800 ml.) and extracted (3x)with ether. Acidification with 6NHCl of the aqueous phase yields3-methyl-indole-1-acetic acid, M.P. 174-176 C.

The latter compound (47.5 g., 0.25 mole) in 1000 ml. of ether is slowlyadded to a stirred mixture of lithium aluminum hydride (12.5 g.) (0.32moles) in 700 ml. of ether. The reaction is kept below 15 C. using anicewater bath. The reaction is stirred for fifteen minutes after theaddition, the excess hydride destroyed with water, and the precipitatecollected. The ether filtrate is washed with water, dried over sodiumsulfate and evaporated under reduced pressure to afford an oil.Chromatography on silica gel using 15% ethylacetate in benzene as eluantgives the title compound, identical with the product of procedure A.

By following the procedure A of Example 1 other indole-l-ethanolintermediates of formula III for example those listed in Examples 6 to55, may be prepared by the appropriate choice of the starting materialof formula II and ethylene oxide derivative. For example, by replacingskatole and ethylene oxide with equivalent amounts of3,7-dimethylindole, R. Robinson et al., cited above, and3-3-dimethyl-1,2-epoxybutane, V. Franzen and H. E. Driesen, cited above,respectively, a mixture of ,B-isopropyl-u,3,7-trimethyl-indole-l-ethanoland a-isopropyl-fl,3,7- trimethyl-indole-l-ethanol, are obtained. Suchmixtures of positional isomers may be separated by fractionaldistillation, fractional recrystallization or chromatography. Lik wise,the replacement of skatole with 3-isopropylindole, R. Robinson et al.cited above, in procedure A of Example 1 yields3-isopropylindole-l-ethanol.

By following procedure B of Example 1 other indolel-ethanolintermediates of formula III in which R and R are hydrogen may beprepared by the appropriate choice of the starting material of formulaII and a-haloacetic acid lower alkyl' ester of formula LCR R CO-O-(lower alkyl) in which L is halo and R and R are hydro gen or loweralkyl. For example, by replacing skatole and ethyl bromoacetate withequivalent amounts of 3-ethylindole, R. Robinson et al., cited above,and 2,3-epoxybutane, F. G. Bordwell and P. S. Landis, J. Amer. Chem.Soc., 79, 1553 (1957), respectively,a,fl-dimethyl-3-ethylindole-l-ethanol is obtained. Likewise thereplacement of skatole with 3-butylindole, R. Robinson et al., citedabove, in the procedure B of Example 1 yields 3-butylindole-1- ethanol.

EXAMPLE 2 3-Methylindole-l-ethanethiol (III; R R R, R and R =H, R =CHand X =SH) Procedure A:

N,N-dicyclohexylcarbodiimide (9.0 g.) is added to a cooled, stirredsolution of 3-methylindole-1-ethanol (3.0 g.) in 30 ml. of .dimethylsulfoxidebenzene (2:1) containing trifluoroa'cetic acid (0.6 ml.) andpyridine (1.12 ml.). The reaction is stirred at room temperature undernitrogen for 5 hours. The reaction mixture is now diluted with 300ml. ofether, followed by the dropwise addition of a solution of oxalic acid(3.78 g.) in 11 ml. of methanol. After thirty minutes, water (300 ml.)is added and the insoluble material is collected. The organic phase iswashed with water (2x 5% aqueous sodium bicarbonate (2X) and water (2x).After drying (MgSO the organic phase is evaporated to yield3-methylindole-1-acetaldehyde. The latter compound is then converted toits corresponding gem-dithiol with hydrogen sulfide and reduced withlithium aluminum hydride according to the method of T. L. Cairns et al.,J. Amer. Chem. Soc. 74, 39 82 (1952), to yield the title compound,

H 3 ,5 2570 cm.

Procedure B;

To a stirred solution of 7.2 g. of 3-methylindole-1- ethanol, describedin Example 1, in 500 ml. of dry ether (ice bath) is slowly added 1.2 ml.of phosphorus tribromide in ml. of dry ether. A dark red oily complexseparates. The reaction mixture is stirred 36-48 hours at roomtemperature, then decomposed with ice and water. The separatedether-layer is quickly Washed with a 10% solution of sodium bicarbonateand with water again, dried over calcium chloride for 2 min., decanted,and dried over magnesium sulfate for 30 min. The filtrate is evaporatedyielding 1-(2-bromoethyl)-3-methylindole.

A solution of 10.4 g. of sodium thiosulfate in 60 ml. of water and 100ml. of ethanol is poured onto 8.6 g. of 1-(2bromoethyl)-3-methylindole.The reaction mixture is stirred and heated at reflux for 3.5 hr.,allowed to cool, and evaporated to dryness. The solid residue isdissolved in boiling isopropanol, dried with a hydrated alkali-aluminumsilicate (Molecular Sieves), and filtered. Chilling of the filtratecauses 6.4 g. of the sodium indolylethyl thiosulfate derivative toprecipitate. This material is collected by filtration and washed withether. The isolated intermediate is heated at reflux with a solution ofsodium hydroxide (9 g. of NaOH, 60 ml. of water, ml. of ethanol) for 3hr. Ethanol is removed under reduced pressure, the aqueous residuediluted with Water and extracted with three portions of ether. Combinedether extracts are washed with water, saturated brine solution, anddried over magnesium sulfate. The filtrate is evaporated, to yield bis-2- 3-methylindolel-yl ethyl] disulfide.

The latter product (1.4 g.) in 100 ml. of dry ether is dropped into astirred suspension of 600 mg. LiAlH in 80 ml. of dry ether. The reactionmixture is heated to reflux for 3 hr. and then kept for 15 hrs. at roomtemperature. Decomposition with 2.8 ml. of water is carried out in astream of nitrogen. After 60 min. of stirring, a white precipitate isfiltered off with suction, the cake was washed with ether, and thefiltrate dried over magnesium sulfate. The clear ether solution isevaporated to give the title compound.

By following procedure A or B of Example 2 other indole-I-ethanethiolintermediates of formula III, for example those described in Examples 57to 106 may be prepared by the appropriate choice of indole-l-ethanolintermediates of formula III. For example, by replacing3-methylindole-1-ethanol with an equivalent amount ofB-isopropyl-a,3,7-trimethylindole-l-ethanol, ,e-isopropyl-a,3,7-trimethyl-indole-l-ethanethiol is obtained. Likewise, by replacing3-methylindole-1-ethanol with an equivalent amount of3-isopropylindole-1-ethanol, 3-isopropylindole- 1-ethanethiol isobtained.

EXAMPLE 3 3,4 Dihydro-l,IO-dimethyl-1H-l.4-oxazino[4,3-a]indolei1-aceticacid (V; R and R =CH R R R R and R =H, X=O and Z=CCH COOH) A mixture ofthe intermediate of formula III, 3-methylindole-l-ethanol (26.5 g., 0.15mole), described in Example 1, in toluene (600 ml.), ethyl acetoacetate(36 g., 0.20 mole) and p-toluenesulfonic acid (2.0 g.) is heated atreflux for 6 hr. using a water separator. The toluene solution is washedwith water, 5% bicarbonate solution, and again with water. The solutionis then dried over sodium sulfate and the solvent evaporated underreduced pressure to give an oil. The oil was subjected to chromatographyon silica gel. Elution with 10% ethyl acetate in benzene andconcentration of the eluate affords the ester, 3,4-dihydro 1,10dimethyl-1H-1,4-oxazino [4,3-a]indole-1-acetic acid ethyl ester, as anoil,

723 1725 Cmf Hydrolysis of this ester to the title compound is effectedas follows: The ester (39.9 g.) is dissolved in 800 ml. of methanolcontaining 22.5 g. of KOH in 20 ml. of water.

15 After stirring for hr. at 50 C. and for 12 hr. at room temperature,the solvent is evaporated under reduced pressure. The residue is takeninto water and washed twice with ether, acidified with 6N HCl andextracted with ether.

16 ether twice, acidified with 6N HCl and extracted three times withether. The ether solution is washed once with water, dried over MfSO,and evaporated, under-reduced pressure to yield a solid. The solid isrecrystallized from The ether solution is Washed once with Water, dried5 ethyl acetate-petroleum ether to give the title compound, (NA SO andevaporated under reduced pressure to afm.p. 115-116 C., NMR (CDCl 61.62(s, 3H), 2.30 (m, ford a solid. The solid is recrystallized frompetroleum 7H), 4.04 (4H), 7.21-7.52 (m. 4H), :93 (1H).

ether to afford the title compound, m.p. 138-l39 C.,

NMR (CDCl 51.75 (s, 3H), 2.86 and 3.18 (d, J=14.5 f

cps" 2H), 4 07 4H) 10 A mixture of the intermediate of, formula III, 5-rneth- An equivalent amount of methyl acetoacetate mayreyhhdole-l-ethanol g), levulihiC acid 9 g-L place ethyl acetoacetate inthe procedure of this Example. 75 of benzene: 8- Of Phosphorus P In thiscase, 3,4-dihydro-l,lO-dimethyl-lH-l,4-oxazino[4, about 9- gofdlatomaceous earth (C e) 1s stlrred 3-a]indole-1-acetic acid methylester is obtained as the maghehcally at room temperature for and t estemat 70 C. for 1 /2 hr. The reaction mixture is filtered. An equivalentamount of propyl acetoacetate may re- The filtrate is Washed thfee timesh NaOH; place ethyl acetoacetate in the procedure of this Example.combined q s p e is Washed twlce wlth h r n In this case, 3 4 1 10- i h1 1H 1 4 i 4, then rendered aCIdIC WHh cold 50% HCl. The aqueous 3a]indo1e 1 acetic acid propyl ester is b i d as h phase is extractedw1t'h chloroform. The chloroform exester. tract is dried (Na SO andevaporated to dryness. Re-

EXAMPLE 4 v crystallization of residue from ethyl acetate-petroleumether affords the title compound, identical to the product 1,10Dimethyl-3,4-dihydro-lH-l,4-oxaz1no[4,3-a]indolef Procedure A f this 1-p p acid R1 and 3, R3, R4, R5 The procedure of Examples 3 and 4(Procedure A) and 2 2 may be followed to prepare other intermediates offor- Procedur A: mula VIII which I1 R R R R R R, X are as e defined IIIthe first instance and Z is COOR or. Alk A mixture of the intermediateof formulaIII, 3 '-methyl- COORm wherein 10 and Alkl are as defined inthe fi t ihdole'lethanol mole), descnbed m Exam instance. Examples ofsuch compounds are listed in Tables P ethyl leYulmate 6 0187 mole) and Iand II. In each of these instances intermediate of forfihesulfomf Q Ybenzene (650 P mula III and ketoester listed therein are used in anequivarefluxed Wlth Stlmhg for 1 with hydrated akahalulhl lent amount tothe intermediates of formula III and ketonum silicate (Molecular sieves#4). The benzene solution esters listed in Examples 3 and 4 (ProcedureNote is Washed W 5% aqueous s follqwed by F that in each of theseinstances an ester is obtained prior Concentrahohs 'f Solutlon a resldueWhlch to hydrolysis. This ester is the corresponding intermediate pa sedthrough a slhca gel column using 15% ethyl acetate of formula v in which2 is cooR or Alk -COOR in benzene to aiford the ester, 3, -d 3f -l, ywherein R is lower-alkyl and Alk is defined in the firstlH-1,4j0XaZ1I1[4,3'a]lhdole'l'proplomc acld ethyl ester instance, theal-kyl portion of said ester being derived asan 011, from the R portionsof the ketoester of formula IV oHoh 1730 Cm employed therein;

max. 7 Likewise, the procedure of Example 4 (Procedure B) This ester(41.9 g.) is dissolved in 650 ml. of methanol may be used to prepare theproducts listed in Tables 1 containing 23 g. of KOH in 50 ml. of waterand heated at and II except that in this case an equivalent amount of 50C. for 1 hr. The solvent is evaporated and the residue the correspondingketoacid of formula IV is used instead taken into water. The aqueousmixture is washed with of the ketoester listed in the table.

- TABLE I Product: (prefix Ketoester of Formula IV, listed below) -3,4-

0 dihydro-lH-l, ll 4-oxazino[4;3-a]- Intermediate of Formula III inwhich X 15 OH R CAlk .C 00 R1" indole-l-(sutfix listed below) 5 H H H HH H3 1 0 02115 1,10-dimcthyl/l carboxylic acid.

6 CH3 H H H H H3 iHa 0 CQH, 1-eLhy1-3,1()-

dimethyl/l carboxylic acid.

7 11- 3 1 H H H 5-CH3 CH3 -Ca 1 CO 0113 1,3-diis pr0py1-8J0.

- dimethvl/l carboxylic acid.

3 CH3 OH; H H 5-OH CH3 HQ 00 CH 8-llydr0Xy-1,3,3;10- Y tetrnmethyU/carboxylic acid.

9 H H H H 7-C2H5 C2H5 n-Ca 7 CO CH3 6,10-dicthyl-1- P ow /l;

. earboxylic acid.

10 H H i-C3H1 H H i-C3H7 C0 CH3 1-cyclopropyl-4,l0-

diisopropyl// carboxylic acid.

11 CH3 CH3 C2H5 Cz a H C2H5 C0 CH3 l-tgyclapentyl-Qdld,

diiiiethyiif carboxylic acid.

12 H H CH3 "H H CH3 H1 CHzCO one!5 1,4,10-trimethy1/7 acetic acid.

13 H H H H H CH3 C2135 CHzCO 02H; l-ethyl-loqriiethylfl 14 H H H H H on;Ii-CsH1 CHiCO C211 lo rh htil igl l-propylll acetic acid, Ml.

. 14 143 0. 15 H H H H H CH3 i-C3H1 CHzCO C2H5 l-iscpropyl-IO-methyl/lacetic acid.

TABLE VIIICoutlnued Number of the example in which starting Product:(prefix listed below)-3,4-dihydro-1H- 1,4thiazino[4,3-a1-indolel-cyelopropyl-4,8,IO-trimethyl-l-(3-[4-(2-hydroxyethyl)1-piperazinyl]-1,1,2,2-tetramethylpropyl1,3,lo-trimethyl-l-[2,2-dipropy113-(1- (l-pyrrolidinyDpropyl].1,10-diethyHA-dimethyI-I-(l,1-dimethyl-3- morpholinopropyl).l-cyclopropyl-l-[l,2-diethyl-3-(4-propyl-1-piperazinyDpropyl]-7-ethoxy-10-ethyl.1,IO-dimethyl-l-[4-(1-pyrrolidiuyl)-butyl]. 1,10-dimethyl-l-{ i-[t(hydroxymethyD-lpiperazinyflbutyl 1-[(Lldiethylt-piperidino)butyl]-1-propyl- 3,3,10-trimethyl.

EXAMPLE 461 N, 1 l -Trimethyl-3,4-dihydro- 1H- 1 ,4-oxazino [4,3 a]indole-1=carboxamido (V: R and R =CH R R R R and R =H, X=0 and Z=CONH.zino[4,3-a]indole-l-acetamide, identical to the product of Example 144,is obtained.

EXAMPLE 462 1,10-Dimethyl-3,4-dihydro-1H-1,4-oxazino- [4,3-a]indolel-prop anol Procedure A:

The acid intermediate of formula V, 1,10-dimethyl-3 ,4- dihydro-IH 1,4oxazino[4,3-a]indole-l-propionic acid (104 g.), described in Example 4,in 100 ml. of THF is slowly added to a stirred mixture of lithiumaluminum hydride (2 g.) in 100 ml. of THF. The reaction is kept at 0 C.using an ice-water bath. After addition of the acid, the excess of thehydride is destroyed with water and the precipitate is collected on afilter pad. The filtrate is evaporated. The residue is taken into etherand the ether phase is washed with water, dried (Na SO and evaporated atreduced pressure to afiord an oil. Chromatography of the oil on silicagel using 1:1 ethyl acetate-chloroform gives the title compound,

" 3129 3610, 3450, 1080 cmf Procedure B:

the ketoalcohol lower alkyl ester, S-acetoxypentan-Z-one.

Note that the procedure of said example includes hydrolysisof theintermediate ester.

EXAMPLE 463 1,10 Dimethyl-3,4-dihydro-lH-l,4 oxazino[4,3 -a]indole-l-propanol (9.5 g.), described in Example 462, is

34 dissolved in dry pyridine (20 ml.). p-Toluenesulfonyl chloride (7.4g.) is added portionwise to the vigorously stirred and cooled solution.The mixture is stirred further at 0 C. for 1 hr., ice and water is thenadded and the aqueous mixture is extracted with ether. The combinedether extracts are washed with 10% ice-coldhydroch'loric acid, water, 5%sodium bicarbonate water and dried (Na SO Concentration of the extractsaflFords 1,10-dimethyl-3 ,4-dihydro-1H-1,4-oxazino[4,3-a]indole-1-propyl tosylate,

max. 011011 1600, 1370, 1190 and 1170 cmf The latter tosylate (12.3 g.)is dissolved in dry acetone ml.) and the resulting solution treated withsodium iodide (15 g.). The mixtureis stirred atroom temperature for 24hr. Most of the acetone is removed at reduced pressure, water and iceare added and the resulting brown-colored solution is extracted withether. The combined ether extracts are washed with 10% sodiumthiosulfate solution, Water and dried (Na SO The solvent is evaporatedunder reduced pressure to give 'ayellow oil. The oil is subjected tochromatography on silica gel and eluted with benzene. Concentration ofthe eluate altords 1,10-dimethyl-1-(3-iodopropyl)-3,4 dihydro 1H-1,4-oxazino[4,3-a] indole, NMR (CDCl 61.59 (3H), 3.13 (2H).

A mixture of the latter compound (10.2 g.) in 100 ml. THF and 40%aqueous 'methylamine (199 ml.) is stirred at room temperature for 6 hr.Most of the tetrahydrofuran is removed at reduced pressure, the milkywater solution is extracted with ether and washed with water until thewater tests neutral. The extract is dried (Na SO and evaporated to yieldthe title compound, identical to the product of Example 285.

By following the procedure of Examples 462 and 463 in sequence but usingas starting material in Example 462 an equivalent amount of theappropriate ester intermediate of formula V (in the case of Procedure A)or an appropriate intermediate of formula III, and appropriateketoalcohol lower alkyl ester of formula IV, described above (in thecase of Procedure B); followed by the use of an appropriate amine offormula HNR iR for example the amines described in Example 107 in theprocedure of Example 463, then the respective compounds of formula I,for example those described in Examples 284 to 460, are obtained.

EXAMPLE 464 1-[2-(Diethylamino)ethyl]-10-methyl-l-propyl 3,4--dihydro-1H-l,4-oxazino[4,3ea]indole [I; R

cn cu cu A solution of triethyloxonium fiuoroborate (3,5 g., 0.0185moles) and the amide of formula V, N,N-diethyl-10-methyl-l-propyl-3,4-dihydro-lH-l,4 -oxazino[4,3 a]-indole-l-acetamide (5.5 g., 0.016 moles), described in Example 130, in100 ml. of methylene chloride is evaporated at reduced pressure and theresidue dissolvedin 50 ml. of absolute ethanol. Sodium borohydride (1.35g., 0.035 moles) is added in portions to the stirred solution at 0 C.When the addition is complete, stirring is continued for 18 hr. at 25C.The solution. is poured into 250 ml. of water and extracted with 3X30ml. portions of ether. The combined extracts are Washed with water,dried (MgSO and evaporated yielding the title compound, identical to theproduct ofExample 307.

Similarly otheramides of formula V, for example those described inExamples 107 to 283, may be reduced'to their correspondingoxazinoindoles of formula I.

35 EXAMPLE 465 1,10-Dimethyl-3,4-dihydro-1H-1,4-oxazino- [4,3-a]indole-l-propionaldehyde N,N-Dicyclohexylcarbodiimide (2.87 g.) is addedto a cooled, stirred solution of the primary alcohol, 1,10- dimethyl 3,4dihydro 1H-1,4-oxazino[4,3-a]indole-lpropanol (1.0 g), described inExample 462, in 10 ml. of dimethyl sulfoxide-benzene (2:1) containingtrifluoroacetic acid (0.18 ml.) and pyridine (0.38 ml.). The reaction isstirred at room temperature under nitrogen for 5 hr. The reactionmixture is now diluted with 100 ml. of ether, followed by the dropwiseaddition of a solution of oxalic acid (1.26 g.) in 6 ml. of methanol.After thirty minutes, water (100 ml.) is added and the insolublematerial is collected. The organic phase is washed with water (2X), 5%aqueous sodium bicarbonate (2X) and water (2X). After drying (MgSO theorganic phase is evaporated to yield an oil. The oil is purified bychromatography on silica gel. Elution with 10% ether in benzene affordsthe title compound as an oil,

Max. 1 'Y Cm.

EXAMPLE 466 1,10 Dimethyl 1 [3 (dimethylamino)propyl] 3,4-

dihydro 1H 1,4 oxazino[4,3 a]indole [I; R and R -=CH R R R R and R =H, X=O and AlkNR R =CH CH CH N CH The product of Example 465 is treated withdimethylamine and perchloric acid according to the method of N. J.Leonard and I. V. Peukstelis, J. Org. Chem., 28, 3021 (1963), to yieldthe corresponding immonium salt. Reduction of the latter compound withsodium borohy- ,dride according to the procedure described by E.

Schenker, Angew. Chem., 73, 81 (1961), affords the title compound,identical to the product .of Example 287.

By following the procedure of Examples 462, 465 and 466 in sequence butusing as starting material in Example 462 an equivalent amount of theappropriate acid intermediate of formula V (in the case of Procedure A)or an appropriate intermediate of formula III, and the appropriateketoalcohol lower alkyl ester of formula IV, described above, (in thecase of Procedure B), followed by the use of an appropriate amine offormula HN'R R for example the amines described in Example 107, in theprocedure of Example 465, then the respective compounds of formula I,for example those described in Examples 284 to 460, are obtained.

EXAMPLE 467 Oxidation of 1,10 dimethyl 3,4 dihydro 1H 1,4-

oxazino[4,3 a]indole 1 propionaldehyde, described in Example 465, withsilver oxide according to the method of Delpine and Bonnet, cited above,affords 1,10 dimethyl 3,4 dihydro 1H 1,4 oxazino [4,3a]indolel-propionic acid, identical to the product of Example 4.

By following the procedure of Examples 462, 465 and 467, in sequence,but using as starting material in Example 462 an equivalent amount ofthe appropriate acid intermediate of formula V (in the case of ProcedureA) or an appropriate intermediate of formula III and appropriateketoalcohol lower alkyl ester of formula IV, described above, (in thecase of Procedure B); then the respective acid compounds of formula V inwhich Z is COOH or Alk COOH wherein Alk is as defined in the firstinstance, for example the products of Examples 5 to 106, are obtained.

EXAMPLE 468 A solution of the aldehyde, 1,10 dimethyl 3,4 'dihydro 1H1,4 oxazino[4,3 a]indole 1 propionaldehyde 1.0 g., described in Example465, aqueous hydroxylamine hydrochloride (5 ml. of 5N) and aqueoussodium acetate (5.0 ml. of 5N) and methanol (10 ml.) is heated at 5060C. for 5 min. and then kept at 4 C. for 16 hr. The precipitate iscollected and recrystallized from ethanol-water to afford thecorresponding oxime of the above aldehyde.

The latter compound (230 mg.) in dry THF (10 ml.) is added dropwise to astirred mixture of lithium aluminum hydride (200 mg.) in 15 ml. of THFat ice bath temperature. The mixture is stirred for 1 hr., during whichtime it is allowed to come to room temperature. Excess lithium aluminumhydride is destroyed by the careful addition of H O/THF (1:1). Insolublematerial is collected on a filter and the filtrate is concentrated. Theconcentrate is taken up in ether. The ether solution is dried (MgSOfiltered and concentrated to afford the title compound, identical withthe product of Example 286.

By following the procedures of Examples 462, 465 and 468, in sequence,but using as starting material in Example 462 an equivalent amount ofthe appropriate acid intermediate of formula V (in the case of ProcedureA) or an appropriate intermediate of formula III together with anappropriate ketoalcohol lower alkyl ester of formula IV, describedabove, then the respective primary amine of formula I is obtained. Morespecifically exemplified, by replacing 1,10 dimethyl 3,4 dihydro 1H 1,4-oxazino[4,3 a]indole l propionic acid with an equiv alent amount of 10methyl 1 propyl 3,4 dihydro- 1H 1,4 oxazino[4,3 a]indole 1 acetic acid,described in Example 14, in the procedure of Example 462 and subjectingthe product thereof to the procedures of Examples 465 and 468, then 1(aminoethyl) 10- methyl 1 propyl 3,4 dihydro 1H 1,4'- oxazino [4,3-

a]indole, identical to the product of Example 304, is obtained.

EXAMPLE 469 To a solution of 3 methylindole 1 ethanol (15 g.) in ml. ofbenzene, 5 iodo 2 pentanone (12 g.) is added. The mixture is heated atreflux with 200 mg. of p-toluenesulfonic acid and hydratedalkali-aluminum silicate (Molecular Sieves No. 4). After one hour 400mg. more of acid is added. After a total of two hours the reaction iscooled, filtered and washed with 5% sodium bicarbonate, water and driedover sodium sulfate. Evapo ration under reduced pressure affords an oil.This oil. is purified by chromatography on silica gel. Elution withbenzene and concentration of the eluate gives the title compound,identical to the compound of the same name described in Example 463.

By following the procedure of Example 469 but using as startingmaterials an appropriate intermediate of formula III described above,together with an appropriate 5, 'y or 5-haloketone of formula IVdescribed above, then the corresponding intermediates of formula V (Z=Alk L in which Alk and L are as described in the first instance) areobtained.

In turn the last said intermediates of formula V may be treatedaccording to conditions described in Example 463 with an appropriateamine of formula HNR R in which R and R are as described in the firstinstance to yield the corresponding oxazinoindoles of formula I, for

1,10 Dimethyl 1 [3-(ethylamino')propyl] -3,4-dihydro-1H-1,4-oxazino+[4,3-a indole (I: R a-'nd'-R"=CH;,, R R R R and R =H, X=Oand A mixture of 3-methylindole-l-ethanol (4.2 g.) and N-(4-oxopentyl)acetamide (317 g), described by L. P. et al., J. Am. Chem.Soc. 89, 3858 (1967), in 300 mll-zdf dry benzene is stirred and heatedat reflux. Water is collected in a Dean-Stark trap. After removel of thewater five drops of boron trifiuoride-etherate is added and the mixturerefluxed 30 min. using the water-separator again. After stirring at roomtemperature overnight the reaction mixture is evaporated to dryness. Thesolid residue is dissolved in chloroform and washed successively with10% aqueous sodium bicarbonate, water, and brine. The chloroformsolution is dried over magnesium sulfate, filtered, and evaporated toyield 1-[3-(acetamido)pr0pyl]-l,lOdimethyl-3,4-dihydro-1H-1,4-oxazino[4,3-a]indole .gg 1650 cmf The latterproduct (2.6 g.) in 80 ml. of dry THF is added to a suspension oflithium aluminum hydride in 200 ml. of THF. The resultant slurry isstirred and heated at reflux for 2 hours, cooled and 2.4 g. of lithiumaluminum hydride is added. The mixture is heated at reflux for 16 hours.The mixture is then decomposed with 22.4 ml. of water added dropwiseover 3 hours while stirring and cooling the mixtures. The precipitate isseparated by filtration. The filtrate is dried (MgSO Removal of the solvent alfords the title compound, identical to the product 7 of Example288.

By following the procedure of Example 470, but using as startingmaterial an equivalent amount of the appropriate starting material offormula III, for example, those described in Examples 1 to 106 and usingan equivalent amount of an appropriate ketoamide of formula describedabove, then the respective secondary amine compounds of formula I areobtained.

EXAMPL'E 471 1,10-Dimethyl 1 (3-nitropropyl)13,4-dihydro-1H-1,4-

oxazino[4,3-a]indole (V; R and R =CH R R R, R and R =H, X=O and Z=CH CHNO ,9 5,9 3450, 1550 cmf Reduction of the latter compound with lithiumaluminum hydride according to the procedure of Example 464 affords1-(3-aminopropyl) 1,10 dimethyl-3,4dihydrolH-l,4-oxazino[4,3-a]indole,identical to the product of Example 286.

38 By followih'g-the procedure of Example 471 including the reductiondescribed therein but using as starting materiel an equivalent amount ofthe appropriate starting material of formula III, for example, thosedescribed in Examples 1 to 100, and using an equivalent: amount of anappropriate nitroketoneof formula in which R R R and R are the same ordifferent selected from the group consisting of hydrogen or lower alkyl;R is hydrogen, lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy,nitro or halo; R is lower alkyl; and X is hydroxy or mercapto; with acompound of formula 0 mil-z in which R is lower alkyl or lowercycloalkyl and Z is CH OCOR or Alk -CI-I OCOR in which R is hydrogen orlower alkyl and Alkl is an alkylene selected from the group consistingof CR R CR R CR R and CR10R11CR12R13CR14R15 h ein R10, R11 R12 R13, R14and R are hydrogen or lower alkyl, (b) separating from the reactionmixture a condensate of the formula wherein R through R''' and Z are asdefined above and X is oxy or thio; (c) subjecting the condensate tohydrolysis in an aqueous alcoholic solution of an alkali to give thecorresponding primary alcohol and separating the corresponding primaryalcohol from the reaction mixture; (d) reacting the primary alcohol withmethane sulfonyl chloride or toluene sulfonyl chloride in the presenceof a strong organic base to give the corresponding mesylate or tosylate;(e) reacting the mesylate or tosylate at a temperature of 40 to C. in aninert organic solvent with at least two molar equivalents of an amine offormula in which R is hydrogen and R is hydrogen or lower alkyl or inwhich R and R are lower alkyl or together with the nitrogen atom towhich they are joined form a heterocyclic amine radical selected fromthe group consisting of l-pyrroliclinyl, piperidino, morpholino,piperazino, 4- (lower alkyl)-1-piperazinyl and 4[hydroxy(l0wer)alkyl- 3833., 57 5 39 40 l-piperazinyl, whereby to prepare -acompound of the inwhich R R R R R R R R R and X are as formula defined herein, and Alk isCH or AIM-CH wherein Alk is as defined herein.

[if 1. R W o 5 References Cited \N R V UNITED STATES PATENTS l AWN,3,676,439 7/1972 Hoffer 260-244 R X HARRY I. MOATZ, Primary Examiner R10 US. 01. X.R.

260-244 R, 246 R, 326.12 R, 326.13 R, 326.16; 424- 246, 248

